2. Zoonotic bacteria complexity and diversity

Zoonotic bacteria are among the most important causes of morbidity and mortality in human, and their importance is recognized and stated by several international and national organizations [34, 35]. Furthermore, given the abundance of scientific proof of their impact on human health, international control and prevention strategies are currently implemented worldwide. In addition, numerous retrospective and prospective studies are conducted by specialized interdisciplinary research groups in order to provide more and updated knowledge on the etiopathogenesis of both already established and emerging or reemerging diseases. The economic consequences cannot be minimized, since the international protocols involve disruptions of national, regional and global trade, and substantial losses associated with animal culling and disposal of the carcasses. To acknowledge the zoonotic importance and the economic impact, certain bacterial diseases are also listed by OIE and require official notification [34]. The most common and important bacterial diseases with confirmed zoonosis status are anthrax, brucellosis, bovine tuberculosis, campylobacteriosis, listeriosis, leptospirosis, salmonellosis, psittacosis [36–38], etc.

Starting with 2010, the WHO, FAO, and OIE identified and issued priority areas that included zoonotic diseases and underlined the need for multidisciplinary collaboration to address health threats at the human-animal-ecosystem interface under the one-health concept. The one-health concept or paradigm allows the comprehensive description of the complex epidemiology in zoonotic diseases. Among the most compelling examples of the One Health paradigm, food-animal-associated zoonoses are distinguished and are monitored worldwide. It is mostly, but not exclusively, the case of foodborne diseases, with top ranked pathogens such as Salmonella, Escherichia coli, Campylobacter [37, 39], etc.

Salmonella serovars and Escherichia coli pathotypes were isolated from many specimens of mammalian, avian, reptilian, and amphibian origin, fish, and insect, as well as from plants, soil, and water origin; hence, the main route of transmission involves consumption of contaminated foods of both animal and vegetal origin: poultry, beef, pork, eggs, milk, fruit, vegetables [37, 39, 40], etc.

These data provide solid bases for the development of safe and effective drugs that can be used

However, mostly due to limitations associated with natural products classical screening methods, large pharmaceutical companies' interest in this category remained relatively low for several years. This particular disadvantage was significantly overcome due to the most recent strategies for natural product screening that involve an integrated multidimensional evaluation of botanical, phytochemical, and biochemical aspects, as well as advanced methods such as metabolomics and proteomics that enable the rapid identification of new compounds

This chapter represents an overview of the most important zoonotic bacteria in terms of complexity, diversity and antimicrobial resistance, and resumes scientific data on bioactivity of medicinal plants against multidrug-resistant zoonotic bacteria isolated from animal cases.

Zoonotic bacteria are among the most important causes of morbidity and mortality in human, and their importance is recognized and stated by several international and national organizations [34, 35]. Furthermore, given the abundance of scientific proof of their impact on human health, international control and prevention strategies are currently implemented worldwide. In addition, numerous retrospective and prospective studies are conducted by specialized interdisciplinary research groups in order to provide more and updated knowledge on the etiopathogenesis of both already established and emerging or reemerging diseases. The economic consequences cannot be minimized, since the international protocols involve disruptions of national, regional and global trade, and substantial losses associated with animal culling and disposal of the carcasses. To acknowledge the zoonotic importance and the economic impact, certain bacterial diseases are also listed by OIE and require official notification [34]. The most common and important bacterial diseases with confirmed zoonosis status are anthrax, brucellosis, bovine tuberculosis, campylobacteriosis, listeriosis, leptospirosis, salmo-

Starting with 2010, the WHO, FAO, and OIE identified and issued priority areas that included zoonotic diseases and underlined the need for multidisciplinary collaboration to address health threats at the human-animal-ecosystem interface under the one-health concept. The one-health concept or paradigm allows the comprehensive description of the complex epidemiology in zoonotic diseases. Among the most compelling examples of the One Health paradigm, food-animal-associated zoonoses are distinguished and are monitored worldwide. It is mostly, but not exclusively, the case of foodborne diseases, with top ranked pathogens such as

Salmonella serovars and Escherichia coli pathotypes were isolated from many specimens of mammalian, avian, reptilian, and amphibian origin, fish, and insect, as well as from plants, soil, and water origin; hence, the main route of transmission involves consumption of contaminated

in human and veterinary medical practice [13, 30, 31].

96 Antimicrobial Resistance - A Global Threat

and production of target molecules, respectively [32, 33].

2. Zoonotic bacteria complexity and diversity

nellosis, psittacosis [36–38], etc.

Salmonella, Escherichia coli, Campylobacter [37, 39], etc.

Other pathogens' transmission is related to occupational hazards, and one of the most resourceful bacterium in this regard is represented by livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA), in particular the clonal complex (CC) 398 [25, 41–43]. Its first description was based on the isolation from pigs, pig handlers, and their close contacts, followed by reports involving livestock and livestock-derived food products in several countries, particularly in regions with high-density pig farming from Europe, Canada, Asia, and the USA [25, 42, 44, 45]. Grounded on recent data, colonization of LA-MRSA among persons occupationally exposed to pigs, cattle, or poultry appears to be very frequent and risk of developing MRSA infections is relatively elevated [41, 42]. The first exposed persons are not only at the risk to develop infections, but also they presumably represent the source for LA-MRSA transmission to household members [43, 46] and other parts of the human population [41], explaining the isolation of LA-MRSA from hospitals and other healthcare facilities' environment.

A substantial scientific database was collected over decades providing relevant information on zoonotic diseases that originate from farmed or food animals [37, 38, 47], but more and more figures suggested pets and wild animals were significant sources and reservoirs of zoonotic bacteria [48–52]. Regarding pets, the great majority of the studies are focused on cats and dogs [53], but lately the range of animal species kept within households diversified to encompass rodents, rabbits, ferrets, birds, amphibians, reptiles, and ornamental fish [49]. Comparing the amount of literature data, pet-associated bacterial zoonoses are considered as a relatively neglected area compared with foodborne zoonoses [49]; thus, future studies are needed to understand the complexity of epidemiological links in these cases.

The main study approach is similar to farmed animals and targets the two main categories of sources: (1) sick animals and (2) asymptomatic carriers, considering that pets may be infected or colonized with a wide variety of bacteria pathogenic to animals and people. With respect to transmission routes, a close contact between pets and owners represents a peculiarity that suggests primarily the direct contact; petting and playing with pets along with licking or minor physical injuries (usually affecting the skin on the hands) may be associated with local or systemic pathologies especially in risk categories that include young, old, pregnant, and immunosuppression individuals. Secondly, the food, water, and the environment may be contaminated by pets' fecal and skin microbiota [54, 55].

The above-mentioned aspects are reunited due to the increasingly popular trend of feeding raw meat-based diets (RMBDs) [56–58], with several studies underlining the serious risks to both animal and human health, given the laboratory confirmed presence of zoonotic bacteria and parasite pathogens in commercial RMBDs. Fresh, refrigerated, and frozen RMBDs may represent the source of Escherichia coli serotype O157:H7, extended-spectrum beta-lactamasesproducing E. coli, Listeria monocytogenes, Salmonella species such as S. typhimurium, S. Heidelberg, and S. Kentucky [54, 56, 57, 59, 60]. Feces appear to represent an important source of Gram-negative bacteria with zoonotic potential, and several studies indicated a positive correlation between the raw meat feeding and Salmonella-active fecal shedding. Although it may not be representative for the general population of dogs, a special canine category was investigated in this regard—the case of dogs that participate in animal-assisted interventions (AAIs), also named "therapy dogs": since these animals commonly interact with immunocompromised people, the risks cannot be minimized [54, 56, 57, 61].

Multiple antibiotic-resistant bacteria emerging in dairy cows' mastitis as a result of extensive/ uncontrolled drug use, biased therapy, horizontal gene transfer, and/or spontaneous genetic mutations pose an increased health risk to humans by contaminating milk and milk products. Virulence genes in connection with antimicrobial define pathogenic, but also certain commensal strains of E. coli, emphasizing the risks of fecal contamination of animal-derived, including milk products, as an important source for human outbreaks. Furthermore, the severeness of illness is increased in E. coli by the association of MDR with Shiga-like toxin (stx1 and stx2) genes' presence. For example, resistance toward several active substances from commercial products recommended for bovine pathologies: penicillin-streptomycin, tetracycline, neomycin, ampicillin, and amoxicillin/clavulanic acid was found to different extents (MAR 0.2–0.80) —was found in 125 isolates sampled from healthy dairy cows. Multidrug-resistant phenotypes (resistance to more than four antimicrobials) were recorded for 12 isolates (9.6%). The molecular analysis pointed out the presence of stx1 gene in case of 20 strains and stx2 for 11 strains, respectively. The presence of Shiga-like toxin genes (stx1 and stx2) and high MAR index highlight the risk associated with human exposure in terms of possible contamination of milk and dairy products provided by the bovine farms. These results support compulsory food hygiene and safety measures throughout the production chain, to minimize or eliminate the contamination risk for the products provided by these farms [Crisan et al., unpublished

Multidrug Resistance in Zoonotic Pathogens: Are Medicinal Plants a Therapeuthic Alternative?

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A study conducted in Canada by Finley et al. [56] indicated for commercially available canine raw food diets, an overall Salmonella prevalence of 21%, with chicken as an ingredient for 67% of the Salmonella-positive diets. Eighteen distinct serotypes displaying resistance toward 12 of the 16 antimicrobials tested, and a predominant pattern of ampicillin and tetracycline resistance entitled the authors to conclude on the need for implementing regulatory guidelines for the production of these diets aimed to reduce or to eliminate the associated risks for pets and

Also, outbreaks of human salmonellosis related to exposure to animal-derived pet treats (pig ear, beef steak patty dog, and pet treats of seafood origin) have been reported in Canada, with the laboratory confirmation of Salmonella contamination in case of mentioned pet treats and identification of the following serotypes: S. Bovismorbificans, S. Give, S. Derby, and S. Typhimurium var. Copenhagen. The overall prevalence of 4% was regarded as lower compared to data reported in 1999, but the isolates showed resistance to up to seven antimicrobials [56]. A significant higher prevalence with 41% (65/158) of samples found positive for Salmonella was reported in case of dog treats derived from pig ears and other animal parts randomly

Updates on the antimicrobial resistance trends are needed in order to select the most suitable choices for the antibacterial therapy particularly in case of methicillin-resistant Staphylococcus aureus (MRSA) infections. Regarded as an opportunist organism, MRSA is responsible not only for localized skin and soft-tissue infections, but also for invasive forms such as septicemia and toxic shock syndrome [45]. Severe clinical outcomes and added costs justify further research

data, 2018].

the contact people.

collected in USA [28].

for alternative treatments.
